Aging and ischemia in gerbils impair spatial memory performance.

Gerbils aged 3 months and 24+ months were subjected to 5 min of global forebrain ischemia and tested in a radial arm maze (1 trial/day, 50 days). Compared with age-matched, sham-operated controls, ischemic animals were impaired on measures of both working and reference memory. Aged animals were impaired on working memory, but not on reference memory, compared with their younger counterparts. Hippocampal CA1 and CA2 regions were significantly and comparably damaged in the 2 ischemic groups but were unaffected by aging. The results suggest that aging and ischemia have functionally similar effects on working memory, but the 2 processes differentially impact reference memory.

Differential effects of amphetamine and haloperidol on recovery after global forebrain ischemia.

Gerbils subjected to sham surgery or to bilateral occlusion of the carotid arteries were given an injection, during the recovery period, of saline, d-amphetamine, or haloperidol. The animals were subsequently tested once daily for 50 days in an eight-arm radial maze. Global forebrain ischemia had no effect on learning to avoid unbaited arms (reference memory), but greatly increased the number of times animals reentered previously visited arms (working memory errors). Gerbils made ischemic and treated with amphetamine reduced working memory errors more rapidly than did saline-treated ischemic gerbils; conversely, animals made ischemic and treated with haloperidol made more working memory errors than the ischemic controls. Although all ischemic animals were hyperactive, the differential radial maze behaviors of the ischemic groups cannot be explained on the basis of increased activity.

Chronic L-deprenyl or L-amphetamine: equal cognitive enhancement, unequal MAO inhibition.

The effect of chronic (4 month), subcutaneous injections of saline, L-deprenyl (0.25 mg/kg), or L-amphetamine (0.25 mg/kg) on the acquisition of a learned spatial habit in a modified Morris Water Maze was investigated in middle aged rats. Injections, given three times weekly starting at 6 months of age, were continued during behavioral testing, which occurred at 10 months of age. The cognitive performance of the middle aged rats was compared to that of 2-month-old control rats. Twenty-four hours after the last behavioral test, the rats were sacrificed and their brains were removed, dissected, and frozen in liquid nitrogen. The activities of MAO-A and MAO-B in the lateral cortex were determined. Results indicate that rats in the L-deprenyl group, the L-amphetamine group, and the young control group all learned the water maze task equally rapidly and significantly faster than rats in the saline group. MAO-A did not differ among the saline, amphetamine, and young control rats, but MAO-B was significantly higher in the middle aged saline and L-amphetamine rats than in the young controls. Both MAO-A and MAO-B activities were significantly lower in the L-deprenyl group than in the other three groups. This indicates that low-dose L-deprenyl can also inhibit MAO-A following chronic SC administration. Moreover, the improved cognitive performance produced by L-deprenyl may not be due to its ability to inhibit MAO-B, but rather to some other effect such as the activation of growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenoceptors and antidepressants: possible 2-phenylethylamine mediation of chronic phenelzine effects.

Effects of chronic administration of antidepressant drugs on beta-adrenoceptor function were assessed. Tricyclics (imipramine 30 mg/kg/day, desipramine 5 and 10 mg/kg/day) and monoamine oxidase inhibitors [(+/-)-tranylcypromine 1 mg/kg/day, phenelzine 5 and 10 mg/kg/day] were administered to Male Sprague-Dawley rats (n = 8), via Alzet 2ML2 osmotic minipumps for 28 days. Pumps were implanted subcutaneously in the interscapular region and replaced after 14 days. On days 21 and 22 motor-suppressant actions of the beta-adrenoceptor agonist salbutamol (3 mg/kg intraperitoneally [IP]) were assessed as a measure of beta-adrenergic receptor sensitivity. On day 28 the animals were killed and their brains used for measurement of drug levels and monoamine oxidase activity. Liver tissue was used to measure the trace amine 2-phenylethylamine. Each drug induced a decrease in the response to salbutamol. With phenelzine the decreased response to salbutamol was not observed at the lower dose. Differences in monoamine oxidase inhibition following phenelzine did not correspond to differential effects on functional beta-adrenergic sensitivity. Levels of 2-phenylethylamine, an endogenous amine that is also a metabolite of phenelzine, were significantly higher in the 10-mg/kg/day phenelzine group. These data suggest that 2-phenylethylamine may be one mediator of the chronic actions of phenelzine on beta-adrenoceptors.

Reciprocal changes in striatal dopamine and beta-phenylethylamine induced by reserpine in the presence of monoamine oxidase inhibitors.

Recent studies have demonstrated that selective monoamine oxidase inhibition may induce changes in brain beta-phenylethylamine availability following lesions. The present study used this approach to re-assess the possible effects of reserpine on striatal concentrations of beta-phenylethylamine and of other amines and selected metabolites. Mice were injected with pargyline (2,200 mg kg-1, 4 h), clorgyline (2 mg kg-1, 2 h) or (-)deprenyl (2 mg kg-1, 2 h) alone or in combination with reserpine (1, 10 mg kg-1, 2 h). Increases in beta-phenylethylamine accumulation were observed in the presence of both (-)deprenyl or pargyline respectively after reserpine except in the case of combined 200 mg kg-1 of pargyline plus 1 mg kg-1 of reserpine. In this condition, a minimal dopamine decrease was observed (to 80% of the concentration of pargyline-treated controls). Increases in beta-phenylethylamine concentration were not observed with reserpine alone (1 or 10 mg kg-1). In the latter condition, the concentrations of beta-phenylethylamine remained at control values due to the activity of monoamine oxidase B. Changes in p-tyrosine, 5-hydroxytryptamine or tryptophan did not consistently accompany increases in beta-phenylethylamine accumulation. Increased beta-phenylethylamine accumulation was always accompanied by the decreases in dopamine induced by reserpine in mice with either non-selective (200 mg kkg-1 pargyline) or type B monoamine oxidase inhibition (2 mg kg-1 pargyline or deprenyl). These data suggest that although the changes in beta-phenylethylamine accumulation may not be due simply to p-tyrosine availability they are related to dopamine levels in the intact striatum.

Modification of nocturnal spontaneous and adrenergic-induced feeding in the rat following either A5 or A7 lesions.

The ingestive profiles of intact, A5 and A7 damaged animals were examined during the 2-hr nocturnal period following onset of the dark cycle. A5, A7 and intact rats consumed comparable amounts of food following initial access to food nocturnally. Sebsequent feeding declined in A5 animals below control values and failed to return to baseline at the end of the nocturnal period examined. A7 damaged rats appeared more resistant to the appetite suppressing effects of initial meal taking and consumed more food than control animals. Only A5 damaged rats were noted to be hyperdipsic during the immediate 10 postoperative days. Intracranial injection of 1-norepinephrine bitartrate (10 ug/ul) into the paraventricular nucleus (PVN) of the hypothalmus produced a reliable facilitation of feeding in A5, A7 and intact rats during the first hour of the dark cycle. A5 rats exhibited the largest increase in feeding elicited by NE administration into the PVN. This feeding response was observed in rats with A5 lesions regardless of whether testing was carried out during the initial hours of the dark cycle or during a predetermined "satiation" test. A5 lesions also effected a marked hyperglycemia while A7 lesions were ineffective in this respect. Taken together these data suggest the A5 and A7 cell groupings regulate spontaneous feeding within a rostrally coursing feeding circuitry and appear to interact with the PVN in the elicitation of noradrenergic feeding.

Selective permeation of the blood-brain barrier as a cause of the anomalous properties of 'atypical'neuroleptics.

Metoclopramide is a widely used anti-emetic drug with potent dopamine-blocking effects on brain structures involved in emesis and prolactin secretion but it is apparently devoid of therapeutic effect in schizophrenia, thus calling into question the supposed role of dopamine blockade in the action of antischizophrenic drugs. This investigation compared the depression of hypothalamic self-stimulation produced by metoclopramide and by a 'typical' neuroleptic, spiroperidol (spiperone), when injected by different routes. Metoclopramide was found to9 be nearly 30 times more potent when administered directly into the brain via the cerebral ventricles than when injected intraperitoneally; on the other hand the potency of spiroperidol was virtually unaffected by the route of administration. The blood-brain barrier is known to be absent from brain sites controlling emesis and prolactin secretion; thus the potency of metoclopramide as an anti-emetic and in releasing prolactin, and its relative ineffectiveness as an antipsychotic can be accounted for by a failure to enter the brain freely except at privileged sites. Thus its anomalous properties are not necessarily inconsistent with the dopamine theory of schizophrenia.

Central cholinergic mechanisms in electrical self-stimulation and in drug-induced tremor in rats.

Oxotremorine, a specific stimulant of central muscarinic acetylcholine receptors, inhibited lateral hypothalamic self-stimulation at a dose-level less than one-tenth of that necessary to produce body tremor. Tremor induced by oxotremorine (0.5 mg/kg) was inhibited by pretreatment with hyoscine (scopolamine) (0.3 mg/kg) or propranolol (20 mg/kg) but not by methylhyoscine (0.3 mg/kg) or apomorphine (0.3 mg/kg). Inhibition of self-stimulation by oxotremorine (.03 mg/kg) was prevented by hyoscine (0.3 mg/kg) but not by any other of the drugs tested and thus constitutes a uniquely specific in vivo model for assessing central antimuscarinic activity. The results confirm the presence of centrally situated ACh receptors eleciting tremor and inhibiting self-stimulation but provide no evidence of an effect on tremor by central adrenergic beta-receptors.

Facilitation of self-stimulation with high doses of amphetamine in the rat.

Rats were trained to self-stimulate by interrupting a photobeam and brain stimulation was maintained for as long as the beam of light was broken. d-Amphetamine sulphate was then administered and response rate and total duration of stimulation were recorded. Both response rate and total duration were elevated by 1.0, 2.0, and 5.0 mg/kg dosages. The 1.4 s/response duration observed with saline was elevated to 2.0 s/response with 2.0 and 5.0 mg/kg doses. It was concluded that amphetamine's effects on self-stimulation are at least partially determined by the response requirements of the task employed.

Thiamin deprivation in ventromedial hypothalamic hyperphagic rats: anorexia, specificity of food aversion, and a dietary consideration.

The anorexic consequence of thiamin deprivation was investigated in ventromedial hypothalamic (VMH) hyperphagic rats under either high-fat or low-fat thiamin-free diet conditions. The low-fat diet maintained feeding significantly longer in thiamin-deprived VMH rats than in intact rats, whereas the hig-fat diet sustained feeding in thiamin-deficient intact rats and accelerated anorexia onset in vitamin B1 deprived VMH rats. This effect was noted under both ad lib and pair-feeding conditions. Thiamin-deprived VMH rats subjected to weight control developed anorexia sooner than intact subjects regardless of the diet employed. The VMH rats fed a high-fat diet failed to resume feeding after thiamin readministration, which was interpreted as a permanent aversion to this diet. The relation between dietary intake and conditioned taste aversion is discussed with reference to the VMH and intact rat.

Reliable method for cannulation of the third ventricle of the rat.

A method for chronic or acute cannulation of the third ventricle of the rat is described. This technique, in which successful cannulation is verified by the aspiration of a minute quantity of cerebrospinal fluid, is simple, reliable and produces minimal tissue distortion. The results of an experiment employing the technique and which compared the effects of direct intrahypothalamic and intraventricular administration of phentolamine on stimulus-bound feeding are briefly described.

Water intoxication death following hypothalamic lesions in the rat.

Rats received large, bilateral lesions of the ventromedial hypothalamus. Water or saline intakes, urine outputs and body temperatures were observed for up to 24 hr after surgery. Fifty percent of the operated animals drank excessively and died within 4-6 hr when permitted access to water. Urine outputs were low and symptoms of water intoxication were evident. When allowed access to saline, outputs rose and the number of animals which survived increased as the saline concentration increased. Body temperatures approached 40 degrees C during drinking, but did not differ from operated animals which refused to drink. It was concluded that the deposition of metallic ions strongly stimulates a hypothalamic drinking system which results in overhydration and water intoxication death.